Despite progress in anti-cytokine therapy the management of rheumatoid arthritis (RA) still requires continuous and aggressive immunosuppression, with a risk for severe side effects. This proposal is designed to explore the mechanisms through which CD8+CD28~CD56+ T suppressor cells inhibit rheumatoid synovitis and how they can be developed into a novel adoptive immunotherapy for this crippling disease Exploiting the preclinical model of human synovium-NOD-SCID chimeras we have identified the adoptive transfer of CD8+CD28~CD56+ T cell clones as a potent means of suppressing synovitis. In vivo and in vitro such CD8+CD28"CD56+ Ts cells downregulate the expression of the costimulatory molecule CD86 on synovial fibroblasts and other synovial APC. Here we hypothesize that CD8*CD28"CD56+ T cells induce unresponsiveness of CD4 T cells by tolerizinq APC in the synovial lesions of RA. leading to long-term inhibition of the disease. Specific Aim 1 is designed to identify the molecular mechanisms through which CD8+CD28~CD56+ Ts cells condition APCs to induce CD4 T cell unresponsiveness. Specific Aim 2 will examine how conditioned APC interact with CD4 T cells, whether a mature immunological synapse is induced and how transmembrane signaling events in CD4 T cells are different from normal activation. In particular, we will examine whether such CD4 T cells have the signature of anergic T cells with enhanced proteolytic degradation of specific signaling proteins In Specific Aim 3 we propose to seek for the critical molecules and pathways that convey immunosuppressive capability onto CD8+CD28~CD56+ T cells, including studies on the role of the CD56 molecule itself. In Specific Aim 4 we will explore whether these specialized CDS T cells have value as biomarkers in predicting disease course and outcome in prospectively followed patients with early RA. Relevance: Rheumatoid arthritis is a crippling disease that is mediated by the immune system. It can be treated but not cured and is costly for the affected individual and society. The immune system possesses cells that naturally inhibit immune-mediated inflammation. The goal of this proposal is to understand how such anti-inflammatory lymphocytes function and how they can be harnessed as novel therapeutic reagents in RA.